Recurrent toxic epidermal necrolysis with two different drugs in a patient with chronic kidney disease–A case report with an atypical presentation

Abstract Toxic epidermal necrolysis (TEN) is a dermatologic emergency usually attributed to drugs. Recurrent episodes of TEN are more common in the pediatric population than in adults. Patients carrying susceptible specific haplotypes, cross‐reactivity between the drugs, and drug metabolites generated by the Cytochrome P450 are the key factors for the recurrent episodes. Chronic kidney disease (CKD) increases the risk of toxic epidermal necrolysis by altering the pharmacokinetics and pharmacodynamics of the drug with comparatively higher mortality in this group of patients. We hereby present an elderly female with 2 episodes of TEN following intake of furosemide at present and Nimesulide 3 years back. Cross‐reactivity between these drugs because of the similar stereochemical structure might have triggered the second episode. The second episode of TEN was milder in presentation with a short latency period without any constitutional symptoms as compared to the first episode. Thus, treating physicians should always consider cross‐reactivity between the chosen drugs in order to prevent subsequent life‐threatening episodes, especially in patients with CKD.

A 60-year-old female, a known case of chronic kidney disease secondary to hypertension, presented to the Emergency Department with generalized ill-defined confluent dusky erythematous tender patches and flaccid bullae on the trunk and extremities with peeling of skin over the mammary region for 3 days (Figure 1D-F).She had erosions on her lips, hard palate, and mucopurulent discharge from the eyes.Skin lesions developed after 16 h of intake of the last dose of furosemide as advised by the treating physician for facial puffiness and pedal edema.
Diagnosis of TEN with acute on chronic kidney disease and Metabolic Acidosis was made with a baseline SCORTEN score of 5. Furosemide was stopped.Patient was admitted to the ICU and was administered intravenous fluids, antibiotics, and a short course of parenteral hydrocortisone along with mucocutaneous care.Vitals, urine output, serum electrolytes, and creatinine were monitored.SCORTEN score was 5 on the third day of admission.Initial reepithelialization of skin lesion was observed after 7 days (Figure 2A-C) and was completed by Day 15 (Figure 2D-F).Serum creatinine levels decreased to 3.2 mg/dL, however, it did not recover completely.
The patient had a similar episode of skin lesions 3 years back following intake of Nimesulide for myalgia and developed extensive mucocutaneous lesions as depicted in Figure 1A-C.She was admitted to our hospital during the previous episode and was managed successfully.
F I G U R E 1 A-C shows mucocutaneous involvement in the first episode of TEN 3 years back which was more severe as compared to the second (recent) episode as shown in D-F.

| DISCUSSION
TEN is a dermatological emergency mediated predominantly by CD8 + T lymphocytes and is associated with an average mortality of 25%. 2,6The recent understanding of epidermal necrolysis in TEN is thought to be an immunedriven pathway mediated by granulysin released by drugspecific cytotoxic CD8 T cells and natural killer cells. 6,7hronic kidney disease increases the risk of adverse drug reactions by changing drug metabolism via altering renal and nonrenal clearance, protein binding, and volume of distribution.Chronic kidney disease has also been found to be a significant strong, independent, prognostic factor for the mortality of patients with SJS/TEN apart from the parameters of SCORTEN. 5 The mortality rate in patients with chronic kidney disease who develop SJS/TEN is comparatively higher and is estimated to be approx.43.7% which was observed in a study conducted by Hung et al. 4 Patients carrying susceptible specific haplotypes, crossreactivity between the drugs with very similar stereochemical structures, and drug metabolites generated by the Cytochrome P450 enzyme complex may influence the recurrence of SJS /TEN. 2 Our patient had two episodes of TEN following intake of Furosemide at present and Nimesulide 3 years back.
The intense literature search revealed a similar chemical structure in Nimesulide and Furosemide.Nimesulide is a cyclooxygenase-2 inhibitor having phenyl and 2-methylsul fonamido-5-nitrophenyl groups. 8Similarly, Furosemide is a diuretic which is a chlorobenzoic acid that consists (furan-2ylmethyl) amino and a sulfamoyl group. 9Both drug contains F I G U R E 2 A-C shows initial reepithelialization over the denuded areas on the 7th day, complete on the 15th day of admission as shown in D-F along with the complete resolution of the oral lesion.
the sulfonamide functional group (R−S(=O) 2 −NR 2 ) which might have triggered the second episode in our patient.
In our patient, the skin lesions in the second episode of TEN appeared earlier as compared to the usual duration reported in the literature.The cause of the short latency period may be attributed to the sensitization of the patient to the sulfonamide group of drugs in the first episode.Similarly, our patient lacked constitutional symptoms and the mucocutaneous involvement was less severe as compared to the first episode as depicted in Figure 1, which might be due to the early presentation of the patient to our center along with early therapeutic intervention.Patient was finally advised to avoid sulpha group containing drugs to prevent the subsequent episodes in the future.

| CONCLUSION
Conventionally, nimesulide and furosemide are two different groups of drugs but an intense literature search revealed that both drugs have a common sulfonamide functional group which triggered the subsequent episode of TEN in our patient, in the setting of chronic kidney disease.Thus, it is important to note that any patient who has had a previous hypersensitivity reaction to a drug is at high risk for recurrence with another drug having a similar chemical structure, and treating physicians should always consider cross-reactivity between the chosen drugs in order to prevent the subsequent life-threatening episodes, especially in patients with chronic kidney disease as the mortality rate is comparatively higher in these group of patients.